CN116209437A - Butylphthalide composition delivered through oral mucosa and application thereof - Google Patents

Abstract

Relates to a butylphthalide composition delivered through oral mucosa and application thereof. The composition comprises 100 parts by weight of butylphthalide, 50-1000 parts by weight of a first surfactant and 0.2-300 parts by weight of a water-soluble polymer. The composition can remarkably improve the dissolution stability of the butylphthalide in oral saliva and increase the oral mucosa absorption of the butylphthalide. The butylphthalide composition delivered through the oral mucosa can be used for preventing or treating tissue pathological injury or nerve cell injury diseases caused by ischemia and hypoxia.

Description

Butylphthalide Compositions Delivered Through the Oral Mucosa and Uses Thereof technical field

The present disclosure relates to a pharmaceutical composition delivered through the oral mucosa and its use, in particular, the present disclosure relates to a butylphthalide composition delivered through the oral mucosa and its use.

Background technique

Butylphthalide (3-n-butylphthalide, also known as apigenin A), and its two enantiomers (D-butylphthalide and L-butylphthalide), are light yellow clear oily liquids with strong volatility , There is a special pungent smell in the mouth, and it has a spicy feeling, and it is insoluble in water.

The patents CN1100097A and CN1623542A of CSPC Enbipu Company disclose the composition of already listed Enbipu soft capsules, which use vegetable oil to solubilize butylphthalide to improve drug solubility. However, oral administration of butylphthalide has a significant hepatic first-pass effect (over 70% is eliminated by metabolism), low bioavailability, high doses of multiple administrations (200 mg (2 soft capsules), TID), and poor patient compliance.

Patent CN1394880A further discloses the composition of the marketed Enbipu injection, which uses cyclodextrin to improve the water solubility of butylphthalide. However, the use of a large amount of cyclodextrin has risks such as nephrotoxicity, and the acute phase is nearly 14 days The injection administration of traditional Chinese medicine has poor patient compliance and is limited in application, so it is not suitable for routine drug use in out-of-hospital patients and patients in the acute stage.

In addition, a variety of other compositions obtained by using butylphthalide solubilization means have been disclosed: such as emulsion solubilized butylphthalide injection or oral preparations (CN100367951, CN100361656), synergistic Solubilized butylphthalide oral tablet (CN200710062273), etc., however, none of the above compositions can avoid the first-pass effect of the oral route and the clinical compliance and safety problems of the injection route.

Therefore, in order to meet the needs of clinical medication, it is necessary to further optimize the existing technology.

Oral mucosal administration, fast absorption, no hepatic first-pass effect, can significantly improve the absorption and bioavailability under non-injection administration routes, and the administration outside the hospital is convenient, avoiding the compliance problem of injection routes. Therefore, the oral mucosal delivery route can improve the clinical drug defects of existing marketed preparations, and is an ideal route of administration.

After retrieval, the butylphthalide composition (CN103169676A) delivered through the oral mucosa has been disclosed at present, but the disclosed sublingual composition technology of butylphthalide still has relatively large defects. It uses semi-solid polyethylene laurate The solid dispersion tablet prepared with glycol glyceride as the matrix dissolves slowly in sublingual saliva (>10 minutes), and is easy to separate out the drug (unstable solubilization), resulting in limited absorption and bioavailability. Moreover, after butylphthalide and lauric acid macrogol glyceride are mixed in the disclosed composition, the effect of adsorption and solidification through lactose and silica gel is not good (there is still the phenomenon of separating out butylphthalide), and the pharmaceutical composition is half Solid tableting has higher requirements on the process of continuous production, and the actual production and storage are more difficult.

In addition, the forms of sublingual compositions disclosed in other patents are mostly in the form of ordinary solid tablet administration, such as the Edaravone sublingual compositions disclosed in patents CN201810797624.9 and CN201780048512.7, and sublingual tablets are selected Conventional excipients, such as mannitol, copovidone or hypromellose, etc., these excipients are combined with edaravone, etc., for sublingual delivery; however, such conventional excipients are not suitable for liquid D The mixing and solidification of phthalide raw materials cannot realize the continuous production of butylphthalide, nor can it improve the absorption of butylphthalide.

Therefore, it is necessary to further improve the technical scheme of the existing butylphthalide sublingual composition, and develop a better new butylphthalide composition to improve the solubilization stability of butylphthalide, and then improve the absorption of butylphthalide through the oral mucosa. Absorption and bioavailability, increase patient compliance and drug safety.

Contents of the invention

The inventors of the present disclosure have found that the dissolution rate of butylphthalide in some surfactants with special structures is good in the research on the absorption promotion mechanism of oral mucosa, and further combining with water-soluble polymers can significantly improve the solubility of butylphthalide in artificial saliva. Good stability, improved dissolution and permeability in vitro, and increased oral mucosal absorption of butylphthalide. On this basis, the inventors have completed the present invention.

An object of the present disclosure is to provide a composition of butylphthalide delivered through the oral mucosa.

Another object of the present disclosure is to provide the use of the butylphthalide composition in the preparation of medicines for preventing or treating histopathological damage or nerve cell damage caused by ischemia and hypoxia.

According to one aspect of the present disclosure, there is provided a butylphthalide composition delivered through oral mucosa, which comprises: 100 parts by weight of butylphthalide, 50-1000 parts by weight of a first surfactant, 0.2-300 parts by weight of a water-soluble polymer parts by weight.

According to another aspect of the present disclosure, it provides the use of the butylphthalide composition in the preparation of a medicament for preventing or treating histopathological damage or nerve cell damage caused by ischemia and hypoxia.

Beneficial effect

According to the butylphthalide composition of the present disclosure, by including the surfactant and the water-soluble polymer, the dilution stability of butylphthalide in saliva can be significantly improved, the rapid precipitation of butylphthalide can be prevented, and the dissolution of drugs can be increased. Permeability, compared with the disclosed solid tablet of CN103169676A, the cumulative permeability of 3h has increased by more than 60%; Compared with commercially available oral soft capsules and common sublingual solid tablets, the absorption of butylphthalide has been significantly improved And bioavailability, its absolute bioavailability (compared to the commercially available infusion preparation) can reach more than 55%, so that at a lower dose, that is, in the form of non-injection administration, it can achieve the effect on ischemic stroke, vascular Prevention and treatment of dementia, muscular spinal atrophy (gradual frostbite), angina pectoris, myocardial infarction, and improvement of medication compliance.

Description of drawings

Fig. 1 is a graph comparing the drug-time curves of the butylphthalide composition of prescription 1 according to an embodiment of the present disclosure, the compositions of comparative prescriptions 1-4 and the commercially available Enbipu soft capsule (dog).

Fig. 2 is a chart showing dissolution-permeation curves of comparative formulation 5 prepared according to the prior art and butylphthalide compositions prepared according to prescription 8, prescription 10 and prescription 11 of the present disclosure.

Fig. 3 is the drug-time curve comparative figure (dog) of the butylphthalide composition prepared according to the contrast prescription 5 of commercially available infusion preparation, prepared according to the prior art and according to the disclosed prescription 8, prescription 10, prescription 11, prescription 18 ).

Detailed ways

In order to enable those with ordinary knowledge in the art to understand the characteristics and effects of the present invention, the terms and terms mentioned in the specification and scope of patent application are generally described and defined below. Unless otherwise specified, all technical and scientific terms used herein have the usual meanings understood by those skilled in the art for the present invention. In case of conflict, the definitions in this specification shall prevail.

As used herein, the terms "comprises", "including", "has", "containing" or any other similar terms are open-ended transitional phrases intended to cover a non-exclusive inclusion. For example, a composition or article containing a plurality of elements is not limited to only those elements listed herein, but may also include other elements not specifically listed but which are generally inherent in the composition or article. Otherwise, unless expressly stated to the contrary, the word "or" means an inclusive "or" and not an exclusive "or". For example, the condition "A or B" is satisfied by any of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), Both A and B are true (or exist). In addition, in this article, the interpretation of the terms "comprises", "comprising", "has", and "containing" should be deemed to have been specifically disclosed and also covers closed forms such as "consisting of" and "consisting essentially of" Conjunctive or semi-closed conjunctions.

In this article, all characteristics or conditions defined in the form of numerical ranges or percentage ranges are only for the sake of brevity and convenience. Accordingly, the description of a numerical range or a percentage range should be considered to encompass and specifically disclose all possible subranges and individual values within the ranges, especially integer values. For example, a range description of "1 to 8" should be deemed to have specifically disclosed all subranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., specifically Subranges are defined by all integer values, and individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc., should be considered to have been specifically disclosed within the range. Unless otherwise indicated, the foregoing method of interpretation is applicable to all content throughout the present invention, whether broad or not.

Where a quantity or other value or parameter is expressed in the form of a range, a preferred range, or a series of upper and lower limits, it is to be understood that any upper or preferred value of that range and lower limit of that range have been specifically disclosed herein. or preferred values, whether or not those ranges are separately disclosed. Further, whenever a numerical range is referred to herein, unless otherwise indicated, such range shall include its endpoints and all integers and fractions within the range.

Herein, under the premise that the object of the invention can be achieved, the numerical value should be understood as having the precision of the effective digit of the numerical value. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

In this article, for the use of Markush group (Markush group) or optional terms to describe the characteristics or examples of the present invention, those skilled in the art should understand the subgroup of all elements in the Markush group or option list Groups or any individual elements may also be used to describe the invention. For example, if X is described as "selected from the group consisting of X ₁ , X ₂ and X ₃ ", it also means that the claim that X is X ₁ and that X is X ₁ and/or X ₂ has been fully described claim. Furthermore, for the use of Markush groups or alternative terms to describe the features or examples of the present invention, those skilled in the art should understand the subgroups or individual elements of all elements in the Markush group or option list Any combination of can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X ₁ , X ₂ and X ₃ ", and Y is described as "selected from the group consisting of Y ₁ , Y ₂ and Y ₃ group" means that the claim that X is X ₁ or X ₂ or X ₃ and Y is Y ₁ or Y ₂ or Y ₃ has been fully described.

The following detailed description is merely exemplary in nature and is not intended to limit the invention and its uses. Furthermore, this document is not to be bound by any theory presented in the preceding prior art or summary, or the following detailed description or examples.

Due to the small area of drug absorption in the oral mucosa and severe saliva washing, the composition administered through the sublingual mucosa needs to meet the characteristics of low dose, dissolution and fast absorption, otherwise it will be lost by saliva washing, resulting in poor absorption and low bioavailability . Oil components (fatty acid glycerides), although they can effectively solubilize insoluble compounds, but the oil is difficult to be digested and absorbed in the oral cavity (different from the gastrointestinal tract, there is no lipase for digesting oil in the oral cavity, etc.), so it dissolves in the oil However, the drug cannot be quickly released and absorbed. CN103169676A has confirmed that butylphthalide solubilized by oils such as glyceryl behenate and glyceryl stearate has a slow dissolution rate and is not suitable for the application of sublingual compositions.

For the poorly soluble drug butylphthalide, maintaining the rapid release and solubilization stability of the drug in saliva is a necessary condition for effective sublingual absorption. Fatty acid-based amphiphilic surfactants (such as PEGylated fatty acid glycerides, which have both hydrophilic and lipophilic properties) are considered to be a better means of promoting oral absorption of poorly soluble drugs. However, the inventor's research has found that the butylphthalide that is solubilized based on the amphiphilic surfactant (such as macrogol glyceride laurate, Gelucire 44/14) based on medium and short-chain fatty acids below C12 alone has After dilution, precipitates will be precipitated immediately, which is not conducive to the rapid absorption of drugs; and the use of an equal amount of amphiphilic surfactants based on C14 or above, especially C18 long-chain fatty acids, can greatly improve the absorption of butylphthalide. The stability in saliva maintains the dissolution stability of butylphthalide for nearly 1 hour (no significant precipitation), which helps to increase the rapid absorption of the drug through the oral mucosa. Further, the inventors have also found that adding a certain amount of polymer to the butylphthalide composition after the solubilization of amphiphilic surfactants based on C14 or above, especially C18 long-chain fatty acids, not only can adjust the combination The dispersion rate of the compound in the saliva can be coordinated with the surfactant to further improve the dissolution stability of butylphthalide in the composition, further improve the oral mucosal absorption of butylphthalide after solubilization, and increase the bioavailability of the drug.

According to one embodiment of the present disclosure, it provides a butylphthalide composition delivered through the oral mucosa, wherein the composition comprises:

100 parts by weight of butylphthalide;

50-1000 parts by weight of the first surfactant, preferably 100-500 parts by weight;

0.2-300 parts by weight of the water-soluble polymer, preferably 0.3-200 parts by weight.

The first surfactant can improve the absorption utilization rate of butylphthalide through oral mucosa. Based on 100 parts by weight of butylphthalide, the amount of the first surfactant is 50-1000 parts by weight, preferably 100-500 parts by weight, such as 120, 150, 180, 200, 250, 300, 350, 400, 450 parts by weight wait. If the amount of the first surfactant is too small, such as less than 50 parts by weight, the stability of the drug in saliva becomes poor, and the precipitation rate becomes faster; and if the amount is too large, such as greater than 1000 parts by weight, the composition The large volume is not conducive to the delivery of oral mucosa such as sublingual mucosa, and it is difficult to achieve short-term absorption of drugs.

The first surfactant refers to an amphiphilic surfactant containing long-chain fatty alcohol or fatty acid (or called long-chain fatty alcohol or fatty acid amphiphilic surfactant or amphiphilic surfactant based on long-chain fatty alcohol or fatty acid). Surfactants or ester surfactants based on long-chain fatty alcohols or fatty acids), for example, can be selected from surfactants based on long-chain fatty acid polyoxyethylene (or polyethylene glycol) esters, long-chain fatty acid-based Surfactants based on polyoxyethylene (or polyethylene glycol) glycerides, surfactants based on long-chain fatty acid phosphoglycerides, surfactants based on long-chain fatty acid sucrose esters, based on long-chain fatty acid polysorbate One or more of, but not limited to. The long chain refers to a straight or branched carbon chain with more than 14 carbon atoms, that is to say, the long chain fatty acid or fatty alcohol refers to a straight or branched chain with a carbon number of more than 14. Branched chain fatty acids or fatty alcohols, such as C14-C22, including but not limited to C15, C16, C17, C18, C19, C20, C21 and other fatty alcohols or fatty acids. In particular, the surfactant is an amphiphilic surfactant based on C18 fatty acids or fatty alcohols.

More specifically, the first surfactant can be selected from polyethylene glycol glyceryl oleate, polyethylene glycol stearate, polyethylene glycol sorbitan oleate (such as Atlas G series surfactants ), polyethylene glycol sorbitan monostearate/oleate (such as Accosperse series surfactants), polyethylene glycol-7-stearate, polyethylene glycol-75-glyceryl stearate Esters, Polyoxyethylene 40 Hydrogenated Castor Oil (Kolliphor RH40), Polyoxyethylene (60) Hydrogenated Castor Oil (Cremphor RH60), Macrogol-12-Hydroxystearate (Kolliphor HS15), Polyoxyethylene 35 Castor One or more of sesame oil (Kolliphor EL/ELPKolliphor EL), polyoxyethylene (20) sorbitan monooleate (Tween80), but not limited thereto.

The water-soluble polymer can play a synergistic role in dissolution and stability in the butylphthalide composition, and it can cooperate with the first surfactant to improve the dilution stability of the active ingredient and improve the dissolution and dissolution of the drug after administration through the oral mucosa , and then improve the effective utilization rate of the active ingredient, and at a lower dose, the blood concentration required for the drug effect can be achieved, thereby improving the patient's compliance.

In an embodiment, the water-soluble polymer may be selected from polyvinylpyrrolidone (PVP, also known as povidone), vinylpyrrolidone/vinyl acetate copolymer (also known as copovidone), polyvinyl alcohol, Carbomer, Hydroxypropyl Cellulose, Hydroxymethyl Cellulose, Hydroxyethyl Cellulose, Sodium Carboxymethyl Cellulose, Sodium Alginate, Chitosan, Carboxymethyl Cellulose, Xanthan Gum, Poloxa One or more of Poloxamer, gelatin, pectin, sodium alginate and polyethylene glycol, more preferably one or more selected from PVP VA64, Poloxamer 407 and xanthan gum.

Based on 100 parts by weight of butylphthalide, the amount of water-soluble polymer can be 0.2 to 300 parts by weight, preferably 0.3 to 200 parts by weight, such as 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70 , 80, 90, 100 parts by weight, etc. If the amount of water-soluble polymer is too small, such as less than 0.2 parts by weight, the synergistic effect of the polymer is weakened, which is not conducive to the synergistic stability of the composition; and if the amount is too large, such as greater than 300 parts by weight, it is necessary Larger amounts of excipients dissolve or disperse the polymer, resulting in a bulkier composition, which is detrimental to buccal delivery of the composition.

According to one embodiment of the present disclosure, the butylphthalide composition may further comprise a second surfactant, and the second surfactant may be selected from surfactants based on medium-chain fatty acids or fatty alcohols, medium-chain alkanes-based One or more of surfactants based on ionic surfactants based on short-chain fatty acids or fatty alcohols. Wherein, based on 100 parts by weight of butylphthalide, the amount of the second surfactant can be 0 to 200 parts by weight, preferably 0 to 100 parts by weight, such as 0, 10, 20, 30, 40, 50, 60, 70, 80, 90 parts by weight, etc.

In the case where the butylphthalide composition contains a second surfactant, preferably, based on 100 parts by weight of butylphthalide, the total amount of both the first and second surfactants can be 50 to 1000 parts by weight, preferably 100-500 parts by weight, such as 100, 125, 150, 180, 200, 250, 300, 350, 400, 450 parts by weight, etc. In addition, the weight ratio of the first and second surfactants can be 1:0.01-5, preferably 1:0.01-1, such as 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, etc. . Within the range of the above weight ratio, the second surfactant can also solubilize butylphthalide without affecting the effect of the first surfactant on solubilizing butylphthalide.

The medium chain refers to a straight or branched carbon chain with 8 to 12 carbon atoms, and the short chain refers to a straight or branched carbon chain with 2 to 7 carbon atoms. The medium-chain fatty acid or fatty alcohol refers to C8-C12 fatty acid or fatty alcohol. The surfactant based on medium-chain fatty acid or fatty alcohol refers to amphiphilic surfactant (or called medium-chain fatty alcohol or fatty acid amphiphilic surfactant or based on medium-chain fatty alcohol or fatty acid) chain fatty alcohols or fatty acid esters or surfactants based on medium chain fatty alcohols or fatty acids), for example, can be selected from macrogolglycerides dodecanoate, macrogolglycerides caprylate One or more of, but not limited to. Dodecanoic acid is, for example, lauric acid, but not limited thereto. The medium-chain alkyl-based ionic surfactant refers to an ionic surfactant containing a C8-C12 alkyl group, such as sodium lauryl sulfate, but is not limited thereto. The short-chain fatty acid or fatty alcohol refers to C2-C7 fatty acid or fatty alcohol. The surfactant based on short-chain fatty acid or fatty alcohol refers to amphiphilic surfactant (or called short-chain fatty alcohol or fatty acid amphiphilic surfactant or based on short-chain fatty alcohol or fatty acid) Surfactants of short-chain fatty alcohols or fatty acid esters or surfactants based on short-chain fatty alcohols or fatty acids)), for example, can be selected from one or more of sucrose acetate isobutyrate, etc., but are not limited to this.

According to one embodiment of the present disclosure, the composition may further include excipients. Based on 100 parts by weight of butylphthalide, the excipient may be used in an amount of 0-1000 parts by weight, preferably 200-800 parts by weight, but not limited thereto.

The excipient can be any excipient suitable for medicaments administered through the oral mucosa in the art, for example, it can be selected from diluents, antioxidants, preservatives, flavoring agents, adsorbents, lubricating agents, One or more of agents, etc., but not limited thereto. Those skilled in the art can select suitable excipients according to needs, and determine the appropriate dosage for use in the butylphthalide composition of the present disclosure.

The amount of the diluent is not particularly limited, and may be a conventional amount in oral mucosal drug delivery preparations. For example, based on 100 parts by weight of butylphthalide, the diluent may be used in an amount of 0-1000 parts by weight, preferably 150-800 parts by weight, but not limited thereto.

The diluent may be selected from one or more of small molecule solvents and oils. The small molecule solvent or oil can make the composition form uniformly dispersed liquid preparations or semi-solid preparations with different fluidity or viscosity, so as to be convenient for patients to use. The small molecule solvent can be selected from ethanol, propylene glycol, glycerol, isopropanol, polyethylene glycol, benzyl alcohol, diethylene glycol ether, ethyl acetate, water, propylene glycol diethyl ester, diethyl malonate, One or more of benzyl benzoate, nitrogen methylpyrrolidone, dimethylacetamide, polyethylene glycol monomethyl ether, diethanolamine, dimethyl sulfoxide, based on 100 parts by weight of butylphthalide, small The molecular solvent may be used in an amount of 0 to 1000 parts by weight, preferably 50 to 1000 parts by weight, but is not limited thereto. The oil may be selected from soybean oil, corn oil, glyceryl linoleate, peppermint oil, ethyl linoleate, peanut oil, cottonseed oil, sesame oil, fish oil, almond oil, peach kernel oil, sunflower oil, safflower oil, One or more of olive oil, coconut oil, palm oil, cocoa bean oil, tea oil, castor oil, sesame oil, and medium-chain fatty acid glycerides. Based on 100 parts by weight of butylphthalide, the amount of grease used may be 0-500 parts by weight, but is not limited thereto. By adding said diluent, the effect of the composition in liquid or semi-solid form suitable for oral mucosal delivery can be adjusted. Research has found that, compared with the disclosed sublingual tablet of butylphthalide, the liquid and semi-solid composition significantly improves the dissolution, dissolution and osmotic absorption of butylphthalide.

The antioxidant and preservative can improve the stability and clinical safety of the composition during long-term storage, so as to prevent oxidation or corruption during long-term storage. The antioxidant can be selected from one of tocopherol, tocopheryl acetate, vitamin E, sodium pyrosulfite, cysteine hydrochloride, sodium bisulfite, ascorbic acid, thioglycerol, ascorbyl palmitate, BHT, and BHA or more, but not limited to this. The preservative can be one or more selected from benzalkonium bromide, benzoic acid and its sodium salt, benzyl benzoate, sorbic acid and its potassium salt, parabens (parabens) , but not limited to this.

The amount of the antioxidant and preservative is not particularly limited, and can be the usual amount in oral mucosal drug delivery preparations. For example, based on 100 parts by weight of butylphthalide, the antioxidant and preservative may be used in an amount of 0-100 parts by weight, preferably 0-50 parts by weight, but not limited thereto.

The flavoring agent in the composition is an additive with mouthfeel correcting effect, and its main purpose is to cover up the special smell and pungent taste of butylphthalide. There is no particular limitation on the flavoring agent, as long as it can be applied in medicine, those skilled in the art can select according to needs, for example, one or more of them can be selected from sweeteners, cooling agents, essences and sesame oils. species, but not limited to this. The flavoring agent can mask the irritating smell or produce a special aroma, and reduce the pungent stimulation of butylphthalide, so as to improve the patient's compliance. The flavoring agent can be selected from sodium saccharin, stevioside, aspartame, neotame, cyclamate, acesulfame potassium, mogroside, xylitol, mannitol, lactose, glucose, sucrose, sucralose, Honey, Peppermint Oil, Menthol, Thymol, Eucalyptol, Curcumin, WS-5, WS-23, Apple Flavor, Lemon Flavor, Vanillin, Tea Flavor, Strawberry Flavor, Pineapple Flavor, Hawthorn Flavor, Glucosyl Steviol Glycoside, Jasmine Absolute, Lemon Oil, Sweet Orange Oil, Winter Herb Oil, Orange Juice Oil, Rose Absolute, Grapefruit Oil, Grapefruit Oil, Borneol, Sodium Caseinate, Alanine, Lemon One or more of acid, acetic acid, malic acid, and trisodium citrate.

The dosage of the flavoring agent is not particularly limited, and may be a conventional dosage in oral mucosal drug delivery preparations. For example, based on 100 parts by weight of butylphthalide, the flavoring agent may be used in an amount of 0-200 parts by weight, preferably 0-150 parts by weight, but not limited thereto.

In the present disclosure, the butylphthalide is selected from one of racemic butylphthalide, L-butylphthalide and D-butylphthalide, preferably L-butylphthalide or racemic butylphthalide.

The composition described in the present disclosure can be filled quantitatively into soft capsules or devices capable of quantitative delivery of drugs (such as quantitative spray or drop devices), and administered via buccal or sublingual mucosa, which is suitable for industrial production. The composition can be selected from dosage forms such as sublingual drops (or solution), sublingual gel, oral spray/aerosol, oral gel or soft capsule.

The single administration dose of the butylphthalide composition is 3-50 mg, preferably 4-40 mg, more preferably 5-30 mg. The daily administration frequency is 1 to 8 times, preferably 2 to 6 times.

According to the present disclosure, the butylphthalide composition using a water-soluble polymer and the first surfactant significantly improves the in vitro dissolution-permeability of butylphthalide. It has been proved by dog oral mucosa administration experiments that it can significantly improve the non-injection The absorption of the route of administration increases the bioavailability of butylphthalide through the oral mucosa. Therefore, compared with other disclosed compositions, the butylphthalide composition described in the present disclosure can achieve the effective plasma concentration of butylphthalide at a lower delivery dose and reduce liver side effects.

According to one embodiment of the present disclosure, wherein, the cumulative in vitro dissolution penetration rate of the butylphthalide composition in artificial saliva for 3 hours reaches more than 60%.

According to an embodiment of the present disclosure, wherein, after the butylphthalide composition is delivered through the oral mucosa, the absolute bioavailability can be increased to more than 55%, preferably more than 65%, more preferably more than 80%.

软胶囊(100mg/粒))，经口腔黏膜给药后的C _max和AUC _0-4h，皆提高2倍以上，部分提高3倍以上，最多可提高4倍以上。 Described butylphthalide composition, compared with equal dosage commercially available butylphthalide soft capsule preparation (Enbipu

Soft capsules (100mg/capsule), _Cmax and AUC _{0-4h after oral mucosal administration,} all increased by more than 2 times, some increased by more than 3 times, and the maximum could be increased by more than 4 times.

注射液 (25mg/100ml))，绝对生物利用度可达55％以上，更多可达65％以上，最多可达80％以上。 Described butylphthalide composition, with respect to the commercially available butylphthalide sodium chloride injection (Enbipu) of equal dosage

Injection (25mg/100ml)), the absolute bioavailability can reach more than 55%, more can reach more than 65%, and can reach more than 80%.

The described butylphthalide composition, compared with the disclosed sublingual tablet composition (CN103169676A Example 1 composition) at the same dose, _{both Cmax} and AUC _0-4h can be increased by 10%, and partially increased by 20% , up to a 30% increase.

Another aspect of the present disclosure relates to the use of the above-mentioned butylphthalide composition according to the present disclosure in the preparation of a medicament for preventing or treating histopathological damage or nerve cell damage caused by ischemia and hypoxia.

Wherein, the disease is selected from one or more of ischemic stroke and its sequelae, vascular dementia, muscular spinal atrophy, angina pectoris, and myocardial infarction.

The butylphthalide composition for oral mucosal delivery according to the present disclosure can be prepared using conventional methods in the art as needed without any particular limitation. In one embodiment, the preparation method comprises the steps of:

a) The diluent dissolves the surfactant, butylphthalide, etc. to obtain the mixture A;

b) the diluent dissolves the polymer, flavoring agent, etc. to obtain mixture B; and

c) under stirring, add the mixture A obtained in b) to the mixture B obtained in a), and further stir, dissolve and mix to obtain the butylphthalide composition in liquid or semi-solid form.

Example

Below in conjunction with embodiment, comparative example, experimental example and description accompanying drawing, accompanying table set forth the present invention, following description is only the illustration to the technical scheme claimed in the present invention, is not any restriction to these technical invention schemes, should not be dealt with The scope of protection of the rights of the present invention constitutes a limit.

In the embodiment, butylphthalide comes from Jinan Chenghui Shuangda, and surfactants, polymers, flavoring agents, excipients, etc., are purchased from BASF, Jiafashi, Chuangle Flavor (Shanghai), Nanjing Weil, etc. .

Preparation method of artificial saliva:

Lactic acid 3.0g, urea 0.2g, sodium chloride 4.5g, potassium chloride 0.3g, sodium sulfate 0.3g, ammonium chloride 0.4g, ultrapure water to 1000ml, 1mol/l sodium hydroxide to adjust the pH to 6.8;

The preparation method of the ethanol-PBS solution of 6% Tween 80:

Sodium chloride 8.0g, potassium chloride 0.2g, sodium dihydrogen phosphate dodecahydrate 3.63g, potassium dihydrogen phosphate 0.24g, add 700ml of pure water, adjust the pH to 7.0 with hydrochloric acid, add 200ml of ethanol, finally add pure water, set Capacity up to 1000ml.

The investigation method of artificial saliva dilution is as follows:

Take 30mg of the equivalent preparation, put it in a 2ml transparent glass bottle, add 1ml of artificial saliva, vortex and mix at 300rpm for 1min, let it stand, and visually observe whether there is precipitation.

The method of investigation of sublingual absorption in dogs is as follows:

Beagle dogs with a body weight of about 10 kg were randomly divided into groups, fasted for 12 hours before administration, and had free access to water.

Commercially available oral soft capsules (Enbipu Soft Capsules (100mg/grain)) were taken orally according to the amount of 100mg/dog, and blood was collected before administration and at 15min, 30min, 1h, 1.5h, 2h, and 4h after administration, and placed in Centrifuge at 4000rpm for 10min in the heparin-treated blood vessel, separate the plasma and analyze it.

The test preparation was administered sublingually, and no drinking water was allowed within 3 minutes after administration, and the dog's mouth was merged to prevent drug loss caused by its tongue sticking out. After 3 minutes of administration, each dog opened its mouth. Before administration and at 5min, 10min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h after administration, blood was collected, placed in heparin-treated blood vessels, centrifuged at 4000rpm for 10min, and plasma was separated and analyzed.

The peak plasma concentration _Cmax is obtained from the highest plasma concentration on the drug-time curve.

AUC _0-4h refers to the area under the drug-time curve from 0h to 4h, which is calculated by the trapezoidal method in Excel.

The absolute bioavailability F is the percentage of AUC _0-4h of the test preparation and the commercially available butylphthalide sodium chloride injection at the same dose.

The in vitro permeability test method is as follows:

Take the medicinal solution of each prescription composition, place it in a dialysis bag of appropriate size, add 1ml of artificial saliva to dilute and disperse, seal it, and place it in a preheated ethanol-PBS solution containing 6% Tween 80 at 37°C, Incubate in a constant temperature shaker (37°C, 100rpm/min), and take 1ml of samples at 30min, 1h, 1.5h, 2h, and 3h respectively (simultaneously add blank solution of equal volume and temperature). The sample solution was centrifuged at 8000rpm for 10min, and the supernatant was taken as the test solution, and the content of free drug dissolved and infiltrated into the PBS solution was detected to evaluate the dissolution-permeation efficiency of the drug.

Example 1: Butylphthalide Compositions Containing First Surfactant Kolliphor EL and Polymer PVP VA64

Table 1

Propylene glycol, Kolliphor EL, apple essence and butylphthalide of prescription quantity are taken by weighing, stir and dissolve, add PVP VA64 and other correctives that dissolve with prescription quantity water, continue to stir (200rpm, 60min) dissolve, obtain clear and transparent solution, have Special aroma.

Take the preparation solution equivalent to 30mg butylphthalide and dilute it with 1ml artificial saliva to observe the stability. The components, dosage and observation results after dilution with artificial saliva of prescription 1 are listed in Table 1 above.

Comparative Example 1: Butylphthalide Compositions Without the First Surfactant or Polymer

Table 2

Weigh the prescribed amount of diluent, apple essence, surfactant, butylphthalide, etc., stir to mix and dissolve, then add the prescribed amount of water-soluble polymer and other flavoring agents, and continue to stir until the solution is clear and transparent without oily liquid visible.

Take the preparation solution equivalent to 30mg butylphthalide and dilute it with 1ml artificial saliva to observe the stability. The components, dosage and observation results after dilution with artificial saliva of comparative prescription 1 to comparative prescription 4 are listed in Table 2 above.

As can be seen from the artificial saliva dilution results in Tables 1 and 2, the stability of prescription 1 containing C18 surfactant Kolliphor EL and polymer PVP VA64 is more stable than that of the comparison prescription 1 without surfactant and polymer, and without polymer. Compositions of the compounds Comparative Formulation 2, Comparative Formulation 3 and Comparative Formulation 4 comprising short (sucrose acetate isobutyrate) or medium chain (e.g. C12 macrogolglycerol laurate) surfactants and polymers, all Significantly increased. It can be seen that the combination of the disclosed water-soluble polymer and the first surfactant can significantly improve the dissolution stability of butylphthalide in saliva.

Experimental Example 1:

With prescription 1 in the embodiment 1 prepared above, comparative prescription 1-comparative prescription 4, carry out the sublingual administration of dog by 30mg/ dog dosage, investigate the impact of surfactant and polymer on the absorption situation of butylphthalide, The results are shown in Figure 1 and Table 3 below. Table 3: Pharmacokinetic parameters of butylphthalide compositions containing surfactant Kolliphor EL and polymer PVPVA64

C _max refers to the highest plasma concentration, AUC _0-4h refers to the area under the plasma concentration-time curve within 0 to 4 hours

The results showed that the AUC _0-4h and C _max of formulation 1 containing C18 surfactant Kolliphor EL and polymer PVP VA64 were better than those of the comparison formulation 1 without surfactant and polymer, and the comparison formulation without polymer 2. Both comparative formulation 3 and comparative formulation 4 containing short or medium chain surfactants and polymers were significantly higher. It can be seen that the combination of the water-soluble polymer described in the present disclosure and the first surfactant can improve the absorption of butylphthalide to the sublingual mucosa.

Embodiment 2 contains the butylphthalide composition of different amounts of the first surfactant

Table 4

For prescriptions 2 to 6, weigh the prescribed amount of diluent, flavoring agent, melted surfactant, polymer, butylphthalide, etc., stir, mix and dissolve until the solution is clear and transparent.

Take the preparation solution equivalent to 30mg butylphthalide and dilute it with 1ml artificial saliva to observe the stability. The compositions, contents and observation results after dilution with artificial saliva of prescriptions 2 to 6 are listed in Table 4 above.

The results showed that the compositions of prescription 2 to prescription 6 were all stable after being exposed to artificial saliva, and there was no obvious precipitation within 3 hours.

The butylphthalide composition under the different polymer types and consumption of embodiment 3

table 5

For prescriptions 7 to 9, weigh the prescribed amount of diluent, polymer, flavoring agent, surfactant and butylphthalide in sequence, stir and mix to dissolve until the solution is clear and transparent, and no oily liquid is visible.

Prescriptions 10 to 12, after dissolving butylphthalide, surfactant and apple essence in propylene glycol, add the prescribed amount of polymer and other flavoring agents dissolved in water, stir and mix, dissolve, degas, and prepare a uniform and transparent condensate Gel-like product.

Take the preparation solution equivalent to 30mg butylphthalide and dilute it with 1ml artificial saliva to observe the stability. The components, contents and observation results after dilution with artificial saliva of prescriptions 7 to 12 are listed in Table 5 above.

The results showed that the compositions of prescriptions 7 to 12 were all stable after being exposed to artificial saliva, and did not precipitate within 3 hours. Embodiment 4 contains the butylphthalide composition of the first and the second surfactant simultaneously

Table 6

For prescriptions 13 to 17, weigh the diluents, flavoring agents, polymers, surfactants, and butylphthalide in the prescribed amount, stir, mix and dissolve until the solution is clear and transparent.

Take the preparation solution equivalent to 30mg butylphthalide and dilute it with 1ml artificial saliva to observe the stability. The components of prescriptions 13 to 17 and the observation results after dilution with artificial saliva are listed in Table 6 above.

The results showed that the compositions of prescriptions 13 to 17 were stable after being exposed to artificial saliva, and no precipitation occurred within 3 hours.

The butylphthalide composition of embodiment 5 different correctives kind and consumption

Table 7

For prescriptions 18 to 22, weigh the diluents, flavoring agents, polymers, surfactants and butylphthalides in the prescribed quantities, stir, mix and dissolve until the solution is clear and transparent.

Take the preparation solution equivalent to 30mg butylphthalide and dilute it with 1ml artificial saliva to observe the stability. The components of formulations 18 to 22 and the observations after dilution with artificial saliva are listed in Table 7 above.

The results showed that the compositions of prescriptions 18 to 22 were all stable after being exposed to artificial saliva, and no precipitation occurred within 3 hours.

Comparative example 2:

According to the prescription and process of Example 1 disclosed in the patent CN103169676A, a butylphthalide buccal tablet with a unit dose of 30 mg based on Gelucire 44/14 was prepared—comparative prescription 5 composition, and the composition of each component is shown in Table 8 below:

Table 8

Preparation method: add butylphthalide, macrogol glycerol laurate, and lactose into the twin-screw extruder according to the prescription of Example 1 disclosed in CN103169676A, and set the section temperature of the extruder to 30°C-60°C -60°C-60°C-45°C, the screw speed of the main engine and the speed of the feeder are both set to 25rpm.

The composition prepared according to the prescription and process in Table 7 above was cooled at room temperature, and the solidification effect was not good. After cooling at 4°C for 12 hours, it was lightly pressed into a semi-solid strip to obtain the composition of Comparative Prescription 5.

Experimental example 2

Comparing prescription 5 and prescription 8 solution, prescription 10 and prescription 11 gel, take a preparation equivalent to 30 mg of butylphthalide, and carry out in vitro dissolution and permeability research according to the above in vitro permeability inspection method, the results are shown in the following table 9 and Figure 2.

Table 9 Dissolution in Vitro of Different Types of Compositions——Permeation Results

time (h) Prescription 8(%) Prescription 10(%) Prescription 11(%) Contrast prescription 5(%) 0.00 0.00 0.00 0.00 0.00 0.50 25.91 14.36 16.36 1.48 1.00 49.88 28.03 31.03 3.69 1.50 65.88 40.37 42.37 4.29 2.00 77.18 48.26 52.26 5.48 3.00 87.09 58.51 62.51 7.64

It can be seen from Table 9 that according to the prescriptions 8, 10, and 11 of the present disclosure, compared with the comparative prescription 5 tablets disclosed in the prior art, the dissolution rate and penetration enhancement rate are significantly improved, and the penetration amount in 3 hours is increased by more than 7 times.

Experimental Example 3

Compare the composition of prescription 5 with the solution of prescription 8, the gels of prescription 10, prescription 11 and prescription 18, and the commercially available infusion preparation (Enbipu injection) 25mg dosage (25mg specification, infusion 60min) , conducted a comparative study on sublingual absorption in dogs, and the results are shown in Table 10 and Figure 3 below.

Table 10

The results showed that after the composition of the comparative prescription 5 was placed under the dog's tongue, it dissolved slowly (more than about 10 minutes for complete dissolution). However, according to the present disclosure, the absolute bioavailability of prescription 8, prescription 10, prescription 11 and prescription 18 compositions solubilized by polymers and long-chain fatty acid ester surfactants is improved by at least 25.5%, prescription 8 and prescription 18 even more than doubled.

The above embodiments are only auxiliary illustrations in nature, and are not intended to limit the embodiments of the application object or the application or use of these embodiments. As used herein, the word "exemplary" means "serving as an example, instance, or illustration." Any exemplary embodiment herein is not necessarily interpreted as being preferred or advantageous over other embodiments.

Furthermore, while at least one illustrative or comparative example has been presented in the foregoing embodiments, it should be understood that a wide variety of variations are possible in the present invention. It should also be appreciated that the embodiments described herein are not intended to limit the scope, use, or configuration of the claimed application object in any way. Rather, the foregoing description will provide those having ordinary skill in the art with a convenient guide to implementing one or more of the described embodiments. Furthermore, various changes may be made in the function and arrangement of elements without departing from the scope defined by claims, and claims include known equivalents and all foreseeable equivalents at the time of filing this patent application. .

Claims (27)

A butylphthalide composition delivered through the oral mucosa, comprising: 100 parts by weight of butylphthalide; 50-1000 parts by weight of the first surfactant, preferably 100-500 parts by weight; and 0.2-300 parts by weight of the water-soluble polymer, preferably 0.3-200 parts by weight. The butylphthalide composition according to claim 1, wherein, the first surfactant is an amphiphilic surfactant containing long-chain fatty alcohol or fatty acid, preferably selected from based on long-chain fatty acid polyoxyethylene ester Surfactants, surfactants based on long-chain fatty acid polyoxyethylene glycerides, surfactants based on long-chain fatty acid phosphoglycerides, surfactants based on long-chain fatty acid sucrose esters, long-chain fatty acid polysorbate-based surfactants One or more of surfactants, the long chain refers to a straight or branched carbon chain with more than 14 carbon atoms, such as a C14-C22 straight or branched carbon chain. The butylphthalide composition according to claim 1, wherein, the first surfactant is an amphiphilic surfactant based on C18 fatty acid or fatty alcohol, Preferably, the first surfactant is selected from the group consisting of polyethylene glycol glyceryl oleate, polyethylene glycol stearate, polyethylene glycol sorbitan oleate, polyethylene glycol sorbitan mono Stearic Acid/Oleate, Macrogol-7-Stearate, Macrogol-75-Glyceryl Stearate, Polyoxyethylene 40 Hydrogenated Castor Oil, Polyoxyethylene(60) Hydrogenated Castor Oil , one or more of polyethylene glycol-12-hydroxystearate, polyoxyethylene 35 castor oil, polyoxyethylene (20) sorbitan monooleate. The butylphthalide composition according to claim 1, wherein, the water-soluble polymer is selected from polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, carbomer, hydroxypropyl cellulose , hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, sodium alginate, chitosan, xanthan gum, poloxamer, gelatin, pectin, alginic acid One or more of sodium and polyethylene glycol, preferably one or more selected from PVP VA64, Poloxamer 407 and xanthan gum. The butylphthalide composition according to claim 1, wherein, the butylphthalide composition further comprises a second surfactant, and the second surfactant is selected from surfactants based on medium-chain fatty acids or fatty alcohols , one or more of ionic surfactants based on medium-chain alkyls, and surfactants based on short-chain fatty acids or fatty alcohols; the medium chain refers to straight or branched chains with 8 to 12 carbon atoms chain carbon chain, the short chain refers to a straight or branched carbon chain with 2 to 7 carbon atoms. The butylphthalide composition according to claim 5, wherein, based on 100 parts by weight of butylphthalide, the amount of the second surfactant is 0 to 200 parts by weight, preferably 0 to 100 parts by weight. The butylphthalide composition according to claim 6, wherein, based on 100 parts by weight of butylphthalide, the total amount of both the first and second surfactants is 50 to 1000 parts by weight, preferably 100 to 1000 parts by weight. 500 parts by weight. The butylphthalide composition according to claim 7, wherein the weight ratio of the first and second surfactants is 1:0.01-5, preferably 1:0.01-1. The butylphthalide composition according to claim 5, wherein, the surfactant based on medium-chain fatty acid or fatty alcohol refers to the amphiphilic surfactant containing medium-chain fatty alcohol or fatty acid, preferably selected from twelve One or more of alkanoic acid macrogolglycerides, caprylic capric acid macrogolglycerides; the ionic surfactant based on the medium-chain alkyl group is a pharmaceutical ionic surfactant containing a medium-chain alkyl group Surfactant, preferably sodium lauryl sulfate; The surfactant based on short-chain fatty acid or fatty alcohol is an amphiphilic surfactant containing short-chain fatty alcohol or fatty acid, preferably sucrose acetate isobutyrate . The butylphthalide composition according to claim 1, wherein, the butylphthalide composition further comprises an excipient; Wherein, based on 100 parts by weight of butylphthalide, the amount of the excipient is 0-1000 parts by weight, preferably 200-800 parts by weight; Wherein, the excipient is one or more selected from diluents, antioxidants, preservatives, and flavoring agents. The butylphthalide composition according to claim 10, wherein the diluent is one or more selected from small molecule solvents and grease. The butylphthalide composition according to claim 11, wherein, based on 100 parts by weight of butylphthalide, the diluent is used in an amount of 0-1000 parts by weight, preferably 150-800 parts by weight. The butylphthalide composition according to claim 11, wherein, the small molecule solvent is selected from ethanol, propylene glycol, glycerin, isopropanol, polyethylene glycol, benzyl alcohol, diethylene glycol ether, ethyl acetate , water, propylene glycol diethyl ester, diethyl malonate, diethanolamine, benzyl benzoate, nitrogen methyl pyrrolidone, dimethyl acetamide, polyethylene glycol monomethyl ether, dimethyl sulfoxide one or more species. The butylphthalide composition according to claim 13, wherein, based on 100 parts by weight of butylphthalide, the small molecule solvent is used in an amount of 0-1000 parts by weight, preferably 50-1000 parts by weight. The butylphthalide composition according to claim 11, wherein, the oil is selected from soybean oil, corn oil, glyceryl linoleate, peppermint oil, ethyl linoleate, peanut oil, cottonseed oil, sesame oil, fish oil , almond oil, peach kernel oil, sunflower oil, safflower oil, olive oil, coconut oil, palm oil, cocoa bean oil, tea oil, castor oil, sesame oil, medium chain fatty acid glycerides. The butylphthalide composition according to claim 15, wherein, based on 100 parts by weight of butylphthalide, the amount of the oil is 0-500 parts by weight. The butylphthalide composition according to claim 10, wherein, the antioxidant is selected from tocopherol, tocopheryl acetate, vitamin E, sodium pyrosulfite, cysteine hydrochloride, sodium sulfite, sodium pyrosulfite, bisulfite One or more of sodium, ascorbic acid, thioglycerol, ascorbyl palmitate, BHT, BHA. The butylphthalide composition according to claim 10, wherein the preservative is selected from benzalkonium bromide, chlorhexidine acetate, benzoic acid and its sodium salt, benzyl benzoate, sorbic acid and its potassium salt , one or more of parabens. The butylphthalide composition according to claim 10, wherein, the excipient includes antioxidants and preservatives, wherein, based on 100 parts by weight of butylphthalide, the amount of antioxidants and preservatives is 0- 100 parts by weight, preferably 0 to 50 parts by weight. The butylphthalide composition according to claim 10, wherein the flavoring agent is one or more selected from sweeteners, cooling agents, essences, and sesame oils, preferably selected from sodium saccharin, stevioside , aspartame, button sweet, cyclamate, acesulfame potassium, mogroside, xylitol, mannitol, lactose, glucose, sucrose, sucralose, honey, peppermint oil, menthol, thymol, eucalyptus Olein, WS-5, WS-23, apple flavor, vanillin, lemon flavor, tea flavor, strawberry flavor, pineapple flavor, hawthorn flavor, glucosyl steviol glycoside, floret jasmine absolute, lemon oil, sweet orange oil, One or more of winter vanilla oil, sweet orange juice oil, rose absolute, grapefruit oil, grapefruit oil, borneol, sodium caseinate, alanine, citric acid, acetic acid, malic acid, and trisodium citrate kind. The butylphthalide composition according to claim 20, wherein, based on 100 parts by weight of butylphthalide, the flavoring agent is used in an amount of 0-200 parts by weight, preferably 0-150 parts by weight. The butylphthalide composition according to claim 1, wherein, the butylphthalide is selected from one of racemic butylphthalide, L-butylphthalide, D-butylphthalide, preferably L-butylphthalide or rac-Butylphthalide. The butylphthalide composition according to claim 1, wherein the dosage form of the composition is selected from sublingual drops, sublingual gel, oral spray/aerosol, oral gel and soft capsule. The butylphthalide composition according to any one of claims 1-23, wherein, the single administration dose of the butylphthalide composition is 3-50 mg, preferably 4-40 mg, more preferably 5-30 mg, each The frequency of daily administration is 1 to 8 times, preferably 2 to 6 times. The butylphthalide composition according to any one of claims 1 to 23, wherein the cumulative dissolution rate of the butylphthalide composition in artificial saliva for 3 hours reaches more than 60%; and/or Wherein, after the butylphthalide composition is delivered through the oral mucosa, the absolute bioavailability is above 55%, preferably above 65%, more preferably above 80%. Use of the butylphthalide composition according to any one of claims 1-23 in the preparation of medicines for preventing or treating histopathological damage or nerve cell damage caused by ischemia and hypoxia. The use according to claim 26, wherein the disease is selected from ischemic stroke, vascular dementia, muscular spinal atrophy, angina pectoris, myocardial infarction.

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